The long-range goals of this project are to better understand the response and consequences of drugs of abuse on subjects that are genetically vulnerable to high alcohol drinking. This is an important area of research in the alcohol field, because many, a large majority in the case of nicotine, individuals who abuse or are dependent on alcohol also abuse other drugs. Moreover, there is evidence that nicotine or cocaine can promote alcoholic relapse and have neurobiological interactions with alcohol. The overall hypotheses to be tested are that (1) selective breeding for disparate alcohol drinking will also produce disparate responses to the effects of other drugs of abuse, and (2) prior exposure to other drugs of abuse will have effects on alcohol drinking and the reinforcing effects of alcohol that are genetically influenced. These hypotheses will be tested in the selectively bred alcohol-preferring (P), alcohol-non-preferring (NP), high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) lines of rats. The objectives of this proposal are to examine the effects of nicotine and cocaine on locomotor activity, alcohol drinking and reinforcement, and mesolimbic dopamine (DA) activity of the selectively bred lines of rats. The results of this study will provide important information on how genetic factors influence a predisposition for high alcohol drinking and abusing other drugs, and how genetic factors that influence alcohol drinking react to other drugs of abuse. Such information could provide insight into common factors that might influence vulnerability to drug and alcohol abuse in certain human populations. This research component interacts with and is dependent upon the Administrative and Animal Production Cores, and also scientifically interacts with the other rat genetic research component. This research component fits within the theme of the IARC in that it is studying genetic effects on the actions of nicotine and cocaine to alter alcohol drinking and the reinforcing effects of ethanol (EtOH).